Over the last decades there has been an increasing interest in understanding the mechanism of changing the three-dimensional structure of macro-molecules, in particular the mechanism for folding proteins in solution and coiling polynucleic acids and analogues thereof. Also, efforts have been made in order to predict or calculate the preferred three-dimensional structure of proteins.
Predictions of the protein secondary structure can be obtained by data driven methods, such as artificial neural network algorithms trained on structural data from the Brookhaven Protein Data Bank. These methods are able to classify up to about approximately 75% of the amino acid residues correctly in a three state prediction: .alpha.-helix, .beta.-sheet, or coil. Earlier statistical methods such as the Chou-Fasmann prediction scheme have lower performance. Alternatively, structural insight can be obtained from homologous proteins using homology modelling. When sufficiently large sequence similarity between two amino acid sequences is present (more than about 25%), it is in most cases possible to build a good model of one protein by analyzing the structure of the other. This method is ineffective when homologous proteins with known structure are unavailable in the databases. Simulation of protein folding based on molecular dynamics algorithms is yet another option to study structure. Due to the computational complexity of this task, molecular dynamics is normally feasible only in constrained versions, where most of the degrees of freedom in the problem are removed.
Until now there has not been established a universal theory for folding of proteins, which fully explains the transition from the unfolded polypeptide chain to the folded protein. Especially, the understanding of the initialization of the transition is crucial when attempts are made to control the folding process. Many proteins fold in less than a second, a time period in which a polypeptide would only be able to scan (visit) a very small fraction of the possible conformations. Consequently, there is no reason to believe that protein folding is based on a trial-and-error protocol. What up to now has been lacking is the understanding of the mechanism which brings the protein across many barriers and leads it towards the folded state. Though some proteins are able to refold in a test tube, cellular factors and cellular conditions are important for the initial folding of proteins. One indication of this comes from biotechnology, where high levels of expression of proteins by recombinant DNA are often obtained, but at the same time much of the resultant material does not fold to its native soluble conformation, but is found as macroscopic insoluble aggregates, or inclusion bodies.